It is known that cyclic adenosine-3′,5′-monophosphate (cAMP) exhibits an important role of acting as an intracellular secondary messenger (Pharmacol. Rev., (1960), 12, 265). Its intracellular hydrolysis to adenosine 5′-monophosphate (AMP) causes number of inflammatory conditions which are not limited to COPD, asthma, arthritis, psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis or colitis. PDE4 inhibitors are designed to inhibit the activity of PDE4, the enzyme which breaks down neuronal cAMP. Studies have shown that administering PDE4 inhibitors can have a restorative effect on memory loss in animal models, including those of Alzheimer's disease (Expert Opin. Ther. Targets (2005) 9(6):1283-1305; Drug Discovery today, 10, number 22, (2005) 1503-1519). The most important role in the control of cAMP (as well as of cGMP (cyclic guanosine monophosphate)) level is played by cyclic nucleotide phosphodiesterases (PDE) which represent a biochemically and functionally highly variable super family of enzymes. Eleven distinct families of cyclic nucleotide phosphodiesterases with more than 25 gene products are currently recognized. Although PDE1, PDE2, PDE3, PDE4, and PDE7 all use cAMP as a substrate, only PDE4 and PDE7 are highly selective for hydrolysis of cAMP. Inhibitors of PDE, particularly the PDE4 inhibitors, such as rolipram or Ro-1724 are therefore known as cAMP-enhancers. Immune cells contain type 4 and type 3 PDE, the PDE4 type being prevalent in human mononuclear cells. Thus the inhibition of phosphodiesterase type 4 has been a target for modulation and, accordingly, for therapeutic intervention in a range of disease processes.
The initial observation that xanthine derivatives, theophylline and caffeine inhibit the hydrolysis of cAMP led to the discovery of the required hydrolytic activity in the cyclic nucleotide phosphodiesterase (PDE) enzymes. Distinct classes of PDE's have been recognized (TIPS, (1990), 11, 150), and their selective inhibition has led to improved drug therapy (TIPS, (1991), 12, 19). Thus it was recognized that inhibition of PDE4 could lead to inhibition of inflammatory mediator release (J. Mol. Cell. Cardiol. (1989), 12 (Suppl. II), S 61) and airway smooth muscle relaxation.
The current approach of targeting PDE4 for alleviating the chronic inflammation associated with COPD is compromised by the dose limiting side effects that are proving difficult to overcome. Theoretically, an alternate strategy would be to use small molecule inhibitors to target other members of the cAMP dependent PDE family that share a common pulmonary cellular distribution to PDE4. It is hypothesized that such an approach would yield compounds with an improved therapeutic ratio. Of the novel cAMP family of proteins discovered so far, PDE7A offers itself as a promising candidate because of its cellular distribution in almost all pro inflammatory and immune cells (Curr Pharm Des. (2006); 12:1-14). Additionally, it has been shown to be a prime modulator of human T cell function as well (Science. (1999) February 5; 283 (5403):848-51).
Thus, dual specificity inhibitors that target both PDE4 and PDE7 would in principle, have an improved spectrum and a wider therapeutic window in the clinics. Compounds with dual PDE4 and PDE7 inhibitory effects have been shown to inhibit T cell function such as cytokine production, proliferation and activation of CD25 expression markers on T cells induced by antigen stimulation (Eur. J. Pharmacol. 541, 106-114, (2006)). Development of dual PDE4-PDE7 inhibitors would yield a novel class of drugs blocking T cell component of a disease partly through PDE7 inhibition as well as possess anti-inflammatory activity. (Eur. J. Pharmacol. 550, 166-172, (2006); Eur. J. Pharmacol. 559, 219-226, (2007)). More importantly, such a pharmacophore would be less limited by nausea and vomiting, a major side effect associated with PDE4 inhibition.
WO 2003/047520 discloses substituted aminomethyl compounds and derivatives thereof, which have been described to be useful as inhibitors of factor Xa. WO 2000/59902 discloses aryl sulfonyls, which have been described to be useful as inhibitors of factor Xa. WO 97/48697 discloses substituted azabicyclic compounds and their use as inhibitors of the production of TNF and cyclic AMP phosphodiesterase. WO 98/57951 and U.S. Pat. No. 6,339,099 describe nitrogen containing heteroaromatics and derivatives, which have been said to be the inhibitors of factor Xa. WO 2005/063767 and WO 2006/001894 disclose indoles, 1H-indazoles, 1,2-benzisoxazoles, and 1,2-benzisothiazoles, preparation and uses thereof. WO 2007/031977 discloses substituted pyrazolo[3,4-b]pyridines as phosphodiesterase inhibitors.